Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

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ABSORPTION OF DRUGS

• Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
• Department of Pharmaceutics
• KLE Universitys College of Pharmacy
• BELGAUm 590010, Karnataka, India
• Cell No 00919742431000
• E-mail bknanjwade_at_yahoo.co.in

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CONTENTS

• Introduction of absorption.
• Structure of the Cell Membrane.
• Gastro intestinal absorption of drugs.
• Mechanism of Drug absorption.
• Factors affecting drug absorption
• Absorption of drugs from non-per oral routes
• Methods of determining absorption
• References.

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Introduction of Absorption

• Definition
• The process of movement of unchanged drug from
  the site of administration to systemic
  circulation.
• There always exist a correlation between the
  plasma concentration of a drug the therapeutic
  response thus, absorption can also be defined
  as the process of movement of unchanged drug from
  the site of administration to the site of
  measurement.
• i.e., plasma.

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Therapeutic success of a rapidly completely
absorbed drug.
?Not only the magnitude of drug that comes into
the systemic circulation but also the rate at
which it is absorbed is important this is clear
from the figure.
Minimum effective conc.
Plasma Drug Conc.
Therapeutic failure of a slowly absorbed drug.
Subtherapeutic level
Time
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CELL MEMBRANE

• Also called the plasma membrane, plasmalemma or
  phospholipid bilayer.
• The plasma membrane is a flexible yet sturdy
  barrier that surrounds contains the cytoplasm
  of a cell.
• Cell membrane mainly consists of
• 1. Lipid bilayer-
• -phospholipid
• -Cholesterol
• -Glycolipids.
• 2. Proitens-
• -Integral membrane proteins
• -Lipid anchored proteins
• -Peripheral Proteins

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LIPID BILAYER
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LIPID BILAYER

• The basic structural framework of the plasma
  membrane is the lipid bilayer.
• Consists primarily of a thin layer of amphipathic
  phospholipids which spontaneously arrange so that
  the hydrophobic tail regions are shielded from
  the surrounding polar fluid, causing the more
  hydrophilic head regions to associate with the
  cytosolic extracellular faces of the resulting
  bilayer.
• This forms a continuous, spherical lipid bilayer
  app. 7nm thick.

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• It consists of two back to back layers
  made up of three types Phospholipid,
  Cholesterol, Glycolipids.
• Phospholipids

?Principal type of lipid in membrane about 75
. Contains polar and non polar region. ?Polar
region is hydrophilic and non polar region is
hydrophobic. Non polar head contain two fatty
acid chain. ?One chain is straight fatty acid
chain.( Saturated ) Another tail have cis double
bond and have kink in tail. ( Unsaturated )
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CHOLESTEROL

• Amount in membrane is 20 .
• Insert in membrane with same orientation as
  phospholipids molecules.
• Polar head of cholesterol is aligned with polar
  head of phospholipids.
• ?FUNCTION
• Immobilize first few hydrocarbons groups
• phospholipids molecules.
• Prevents crystallization of hydrocarbons
• phase shift in membrane

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NON - POLAR HYDROCARBON CHAIN
OH
RIGID STEROID REGION
POLAR REGION
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GLYCOLIPIDS

• Another component of membrane lipids present
  about 5 .
• Carbohydrate groups form polar head.
• Fatty acids tails are non polar.
• Present in membrane layer that faces the
  extracellular fluid.
• This is one reason due to which bilayer is
  asymmetric.
• FUNCTIONS
• Protective
• Insulator
• Site of receptor
  binding

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COMPOSITION OF PROTEINS
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INTEGRAL PROTEINS

• Also known as Transmembrane protein.
• Have hydrophilic and hydrophobic domain.
• Hydrophobic domain anchore within the cell
  membrane and hydrophilic domain interacts with
  external molecules.
• Hydrophobic domain consists of one, multiple or
  combination of a helices and ß sheets protein
  mofits.
• Ex. Ion Channels, Proton pump, GPCR.

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LIPID ANCHORED PROTEIN

• Covalently bound to single or multiple lipid
  molecules.
• Hydrophobically inert into cell membrane anchor
  the protein.
• The protein itself is not in contact with
  membrane.
• Ex. G Proteins.

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PERIPHERAL PROTEINS

• Attached to integral membrane proteins OR
  associated with peripheral regions of lipid
  bilayer.
• Have only temporary interaction with biological
  membrane.
• Once reacted with molecule, dissociates to carry
  on its work in cytoplasm.
• Ex. Some Enzyme, Some Hormone

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GASTRO INTESTINAL ABSORPTION OF DRUGS
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• Stomach
• The surface area for absorption of drugs is
  relatively small in the stomach due to the
  absence of macrovilli microvilli.
• Extent of drug absorption is affected by
  variation in the time it takes the stomach to
  empty, i.e., how long the dosage form is able to
  reside in stomach.
• Drugs which are acid labile must not be in
  contact with the acidic environment of the
  stomach.
• Stomach emptying applies more to the solid dosage
  forms because the drug has to dissolve in the GI
  fluid before it is available for absorption.
• Since solubility dissolution rate of most drugs
  is a function of pH, it follows that, a delivery
  system carrying a drug that is predominantly
  absorbed from the stomach, must stay in the
  stomach for an extended period of time in order
  to assure maximum dissolution therefore to
  extent of absorption.

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• Small Intestine
• The drugs which are predominantly absorbed
  through the small intestine, the transit time of
  a dosage form is the major determinant of extent
  of absorption.
• Various studies to determine transit time
• Early studies using indirect methods placed the
  average normal transit time through the small
  intestine at about 7 hours.
• These studies were based on the detection of
  hydrogen after an oral dose of lactulose.
  (Fermentation of lactulose by colon bacteria
  yields hydrogen in the breath).

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Small Intestine

• Newer studies suggest the transit time to be
  about 3 to 4 hours.
• Use gamma scintigraphy.
• Thus, if the transit time in small intestine for
  most healthy adults is between 3 to 4 hours, a
  drug may take about 4 to 8 hours to pass through
  the stomach small intestine during fasting
  state.
• During the fed state, the small intestine transit
  time may take about 8 to 12 hours.

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• Large intestine
• The major function of large intestine is to
  absorb water from ingestible food residues which
  are delivered to the large intestine in a fluid
  state, eliminate them from the body as semi
  solid feces.
• Only a few drugs are absorbed in this region.

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MECHANISM OF DRUG ABSORPTION

• Passive diffusion
• Pore transport
• Carrier- mediated transport
• a) Facilitated diffusion
• b) Active transport
• Ionic or Electrochemical diffusion
• Ion-pair transport
• Endocytosis

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PASSIVE DIFFUSION

• Also known as non-ionic diffusion.
• It is defined as the difference in the drug
  concentration on either side of the membrane.
• Absorption of 90 of drugs.
• The driving force for this process is the
  concentration or electrochemical gradient.

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• Passive diffusion is best expressed by Ficks
  first law of diffusion which states that the drug
  molecules diffuse from a region of higher
  concentration to one of lower concentration
  until equilibrium is attained the rate of
  diffusion is directly proportional to the
  concentration gradient across the membrane.
• dQ D A Km/w (CGIT C)
  dt
  h
• Certain characteristic of passive diffusion can
  be generalized.
• Down hill transport

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• Greater the surface area lesser the thickness
  of the membrane, faster the diffusion.
• Equilibrium is attained when the concentration on
  either side of the membrane become equal.
• Greater the membrane/ water partition coefficient
  of drug, faster the absorption.
• Passive diffusion process is energy independent
  but depends more or less on the square root of
  the molecular size of the drugs.
• The mol. Wt. of the most drugs lie between 100 to
  400 Daltons which can be effectively absorbed
  passively.

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Pore transport

• Also known as convective transport, bulk flow or
  filtration.
• Important in the absorption of low mol. Wt. (less
  than 100). Low molecular size (smaller than the
  diameter of the pore) generally water-soluble
  drugs through narrow, aqueous filled channels or
  pores in the membrane structure.
• e.g. urea, water sugars.
• The driving force for the passage of the drugs is
  the hydrostatic or the osmotic pressure
  difference across the membrane.

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• The rate of absorption via pore transport depends
  on the number size of the pores, given as
  follows
• dc N. R2. A . ?C
• dt (?) (h)
• where,
• dc rate of the absorption.
• dt
• N number of pores
• R radius of pores
• ?C concentration gradient
• ? viscosity of fluid in the pores

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CARRIER MEDIATED TRANSPORT MECHANISM

• Involves a carrier (a component of the membrane)
  which binds reversibly with the solute molecules
  to be transported to yield the carrier solute
  complex which transverses across the membrane to
  the other side where it dissociates to yield the
  solute molecule
• The carrier then returns to its original site to
  accept a fresh molecule of solute.
• There are two types of carrier mediated transport
  system
• a) facilitated diffusion
• b) active transport

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a) Facilitated diffusion

• This mechanism involves the driving force is
  concentration gradient.
• In this system, no expenditure of energy is
  involved (down-hill transport), therefore the
  process is not inhibited by metabolic poisons
  that interfere with energy production.

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• Limited importance in the absorption of drugs.
• e.g. Such a transport system include entry of
  glucose into RBCs intestinal absorption of
  vitamins B1 B2.
• A classical example of passive facilitated
  diffusion is the gastro-intestinal absorption of
  vitamin B12.
• An intrinsic factor (IF), a glycoprotein produced
  by the gastric parietal cells, forms a complex
  with vitamin B12 which is then transported across
  the intestinal membrane by a carrier system.

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b) Active transport

• More important process than facilitated
  diffusion.
• The driving force is against the concentration
  gradient or uphill transport.
• Since the process is uphill, energy is required
  in the work done by the barrier.
• As the process requires expenditure of energy, it
  can be inhibited by metabolic poisons that
  interfere with energy production.

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• If drugs (especially used in cancer) have
  structural similarities to such agents, they are
  absorbed actively.
• A good example of competitive inhibition of drug
  absorption via active transport is the impaired
  absorption of levodopa when ingested with meals
  rich in proteins.
• The rate of absorption by active transport can be
  determined by applying the equation used for
  Michalies-menten kinetics
• dc C.(dc/dt)max
• dt Km C
• Where,
• (dc/dt)max maximal rate of drug absorption at
  high drug
  concentration.
• C concentration of drug available
  for absorption
• Km affinity constant of drug for the
  barrier.

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IONIC OR ELECTROCHEMICAL DIFFUSION

• This charge influences the permeation of drugs.
• Molecular forms of solutes are unaffected by the
  membrane charge permeate faster than ionic
  forms.
• The permeation of anions cations is also
  influenced by pH.
• Thus, at a given pH, the rate of permeation may
  be as follows
• Unionized molecule gt anions gt cations

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• The permeation of ionized drugs, particularly the
  cationic drugs, depend on the potential
  difference or electrical gradient as the driving
  force across the membrane.
• Once inside the membrane, the cations are
  attached to negatively charged intracellular
  membrane, thus giving rise to an electrical
  gradient.
• If the same drug is moving from a higher to lower
  concentration, i.e., moving down the electrical
  gradient , the phenomenon is known as
  electrochemical diffusion.

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ION PAIR TRANSPORT

• It is another mechanism is able to explain the
  absorption of such drugs which ionize at all pH
  condition.

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• Transport of charged molecules due to the
  formation of a neutral complex with another
  charged molecule carrying an opposite charge.
• Drugs have low o/w partition coefficient values,
  yet these penetrate the membrane by forming
  reversible neutral complexes with endogenous
  ions.
• e.g. mucin of GIT.
• Such neutral complexes have both the required
  lipophilicity as well as aqueous solubility for
  passive diffusion.
• This phenomenon is known as ion-pair transport.

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ENDOCYTOSIS

• It involves engulfing extracellular materials
  within a segment of the cell membrane to form a
  saccule or a vesicle (hence also called as
  corpuscular or vesicular transport) which is then
  pinched off intracellularly.

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• In endocytosis, there are three process
• A) Phagocytosis
• B) Pinocytosis
• C) Transcytosis

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A) Phagocytosis
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B) Pinocytosis

• This process is important in the absorption of
  oil soluble vitamins in the uptake of nutrients.

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C) Transcytosis

• It is a phenomenon in which endocytic vesicle is
  transferred from one extracellular compartment to
  another.

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Diagram Representing Absorption, Distribution,
Metabolism and Excretion The ultimate goal is
to have the drug reach the site of action in a
concentration which produces a pharmacological
effect. No matter how the drug is given (other
than IV) it must pass through a number of
biological membranes before it reaches the site
of action.
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DIFFUSION THROUGH MEMBRANES

• Rate dependent on polarity and size.
• Polarity estimated using the partition
  coefficient.
• The greater the lipid solubility the faster the
  rate of diffusion
• Smaller molecules (nm/A0) penetrate more rapidly.
• Highly permeable to O2, CO2, NO and H2O .
• Large polar molecules sugar, aa, phosphorylated
  intermediates poor permeability
• These are essential for cell function must be
  actively transported

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MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES
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BIOLOGICAL FACTORS

• Penetration Of Drugs Through Gastro-intestinal
  Tract
• Penetration Of Drugs Through Blood Brain
  Barrier
• Penetration Of Drugs Through Placental Barrier
• Penetration Of Drugs Through Across The Skin
• Penetration Of Drugs Through The Mucous
  Membrane Of The Nose, Throat, Trachea, Buccal
  Cavity, Lungs ,Vaginal And Rectal Surfaces
• PHYSIOLOGICAL FACTORS
• Gastrointestinal (Gi) Physiology
• Influence Of Drug Pka And Gi Ph On Drug
  Absorbtion
• Git Blood Flow
• Gastric Emptying
• Disease States

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PENETRATION OF DRUGS THROUGH GASTRO-INTESTINAL
TRACT

• The Git barrier that separates the lumen of the
  stomach and intestine from systemic circulation
  and is composed of lipids, proteins and
  polysaccharides.
• Git mucosa is a semi permeable membrane across
  which various nutrients like Carbohydrates, Amino
  acids, Vitamins and foreign substances are
  transported and absorbed into the blood by
  various mechanisms like
• 1. Passive diffusion
• 2. Pore transport
• 3. Facilitated transport
• 4. Active transport
• 5. Pinocytosis

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1. PASSIVE DIFFUSION

• Major process for absorption of more than 90 of
  drugs
• Diffusion follows Ficks law
• The drug molecules diffuse from a region of
  higher concentration to a region of lower
  concentration till equilibrium is attained.
• Rate of diffusion is directly proportional to the
  concentration gradient across the membrane.
• Factors affecting Passive diffusion
• Diffusion coefficient of the drug
• Related to lipid solubility and molecular wt.
• Thickness and surface area of the membrane
• Size of the molecule

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2. PORE TRANSPORT

• It involves the passage of ions through Aq. Pores
  (4-40 A0)
• Low molecular weight molecules (less than 100
  Daltons) eg- urea, water, sugar are absorbed.
• Also imp. In renal excretion, removal of drug
  from CSF and entry
• of drugs into liver.

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3. FACILITATED DIFFUSION

• Carrier mediated transport (downhill transport)
• Faster than passive diffusion
• No energy expenditure is involved
• Not inhibited by metabolic poisons
• Important in transport of Polar molecules and
  charged ions that dissolve in water but they can
  not diffuse freely across cell membranes due to
  the hydrophobic nature of the phospholipids.
• Eg. 1. entry of glucose into RBCs
• 2. intestinal absorption vitamin B1 ,B2
• 3. transport of amino acids thru
  permeases

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4. ACTIVE TRANSPORT

• Carrier mediated transport (uphill transport)
• Energy is required in the work done by the
  carrier
• Inhibited by metabolic poisons
• Endogenous substances that are transported
  actively include sodium, potassium, calcium,
  iron, glucose, amino acids and vitamins like
  niacin, pyridoxin.
• Drugs having structural similarity to such
  agents are absorbed actively
• Eg. 1. Pyrimidine transport system absorption
  of 5 FU
• and 5 BU
• 2. L-amino acid transport system
  absorption of
• methyldopa and levodopa

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5. PINOCYTOSIS

• Pinocytosis ("cell-drinking")
• Uptake of fluid solute.
• A form of endocytosis in which small particles
  are brought into the cell in the form of small
  vesicles which subsequently fuse with lysosomes
  to hydrolyze, or to break down, the particles.
• This process requires energy in the form of
  (ATP).
• Polio vaccine and large protein molecules are
  absorbed by pinocytosis

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PENETRATION OF DRUGS THROUGH BLOOD BRAIN BARRIER

• A stealth of endothelial cells lining the
  capillaries.
• It has tight junctions and lack large intra
  cellular pores.
• Further, neural tissue covers the capillaries.
• Together , they constitute the so called BLOOD
  BRAIN BARRIER
• Astrocytes Special cells / elements of
  supporting tissue found at the base of
  endothelial membrane.
• The blood-brain barrier (BBB) is a separation of
  circulating blood and cerebrospinal fluid (CSF)
  maintained by the choroid plexus in the central
  nervous system (CNS).

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Since BBB is a lipoidal barrier, It allows
only the drugs having high o/w partition
coefficient to diffuse passively where as
moderately lipid soluble and partially ionised
molecules penetrate at a slow rate.
Endothelial cells restrict the diffusion of
microscopic objects (e.g. bacteria ) and large or
hydrophillic molecules into the CSF, while
allowing the diffusion of small hydrophobic
molecules (O2, hormones, CO2). Cells of the
barrier actively transport metabolic products
such as glucose across the barrier with specific
proteins.

• Various approaches to promote crossing the BBB
  by drugs
• Use of Permeation enhancers such as dimethyl
  sulfoxide (DMSO)
• Osmotic disruption of the BBB by infusing
  internal carotid artery
• with mannitol
• Use of Dihydropyridine redox system as drug
  carriers to the brain
• ( the lipid soluble dihydropyridine is linked as
  a carrier to the polar
• drug to form a prodrug that rapidly crosses the
  BBB )

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PENETRATION OF DRUGS THROUGH PLACENTAL BARRIER

• Placenta is the membrane separating fetal blood
  from the maternal blood.
• It is made up of fetal trophoblast basement
  membrane and the endothelium.
• Mean thickness (25 µ) in early pregnancy and
  reduces to (2 µ) at full term
• Many drugs having mol. wt. lt 1000 daltons and
  moderate to high lipid solubility e.g. ethanol,
  sulfonamides , barbiturates, steroids ,
  anticonvulsants and some antibiotics cross the
  barrier by simple diffusion quite rapidly .
• Nutrients essential for fetal growth are
  transported by carrier mediated processes

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PENETRATION OF DRUGS THROUGH ACROSS THE SKIN

• Skin is composed of three primary layers
• the epidermis , which provides waterproofing and
  serves as a barrier to infection
• the dermis , which serves as a location for the
  appendages of skin and
• the hypodermis (subcutaneous adipose layer).
• The stratum corneum is the outermost layer of
  the epidermis and is composed mainly of dead
  keratinised cells (from lack of oxygen and
  nutrients). It has a thickness between 10 - 40
  µm.
• The dermis is the layer of skin beneath the
  epidermis. It contains the hair follicles, sweat
  glands, sebaceous glands, apocrine glands,
  lymphatic vessels and blood vessels.
• Hypodermis - Its purpose is to attach the skin
  to underlying bone and muscle as well as
  supplying it with blood vessels and nerves. The
  main cell types are fibroblasts, macrophages and
  adipocytes (the hypodermis contains 50 of body
  fat).

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• ROUTES OF PENETRATION
• Through follicular region
• Through sweat ducts
• Through unbroken stratum corneum
• FACTORS IN SKIN PERMEATION
• Thickness of the skin layer
• (Thickest on palms and soles thinest on the
  face)
• Skin condition permeability of skin is affected
  by age, disease state or injury.
• Skin temp. permeability increases with increase
  in temp.
• Hydration state
• APPROACHES TO ENHANCE SKIN PERMEATION
• Innuction
• Iontophoresis
• Sonophoresis
• Magnetophoresis

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Penetration Of Drugs Through The Mucous Membrane
Of The Nose, Throat, Trachea, Buccal Cavity,
Lungs ,Vaginal And Rectal Surfaces

• The barrier for the drug absorption is the
  capillary endothelial membrane which is lipoidal
  and consists of pores .
• Thus, lipid soluble drugs can easily penetrate by
  diffusion and smaller drug molecules can
  penetrate by pore transport.

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Gastrointestinal (GI) Physiology
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• SMALL INTESTINE
• Major site for absorption of most drugs due to
  its large surface area (0.33 m2 ).
• It is 7 meters in length and is approximately
  2.5-3 cm in diameter.
• The Folds in small intestine called as folds of
  kerckring, result in 3 fold increase in surface
  area ( 1 m2).
• These folds possess finger like projections
  called Villi which increase the surface area 30
  times ( 10 m2).
• From the surface of villi protrude several
  microvilli which increase the surface area 600
  times ( 200 m2).
• Blood flow is 6-10 times that of stomach.
• PH Range is 57.5 , favourable for most drugs to
  remain unionised.
• Peristaltic movement is slow, while transit time
  is long.
• Permeability is high.
• All these factors make intestine the best site
  for absorbtion of most drugs.

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INFLUENCE OF DRUG pKa AND GI PH ON DRUG
ABSORBTION
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GIT BLOOD FLOW

• It plays an imp. role in drug absorption by
  continuously maintaining the conc. Gradient
  across the epithelial membrane
• Polar molecules that are slowly absorbed show
  no dependence on blood flow
• The absorption of lipid soluble drugs and
  molecules that are small enough to easily
  penetrate through Aq. pores is rapid and highly
  dependent on rate of blood flow

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GASTRIC EMPTYING

• The process by which food leaves the stomach and
  enters the duodenum.
• It is a RDS in drug absorbtion.
• Rapid Gastric Emptying Advisable when
• Rapid onset of action is desired eg. Sedatives
• Dissolution occurs in the intestine eg. Enteric
  coated tablets
• Drugs not stable in gi fluids eg. penicillin G
• Drug is best absorbed from small intestine eg.
  Vitamin B12
• Delay in Gastric Emptying recommended when
• Food promotes drug dissolution and absorbtion eg.
  Gresiofulvin
• Disintegration and dissolution is is promoted by
  gastric fluids

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Factors affecting Gastric Emptying
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DISEASE STATES

• CHF decreases blood flow to the Git, alters GI
  PH, secretions and microbial flora.
• Cirrhosis influences bioavailability mainly of
  drugs that undergo considerable 1st pass
  metabolism eg. Propranolol
• Git infections like cholera and food poisoning
  also result in malabsorbtion.

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PHYSIO-CHEMICAL FACTORS

• PHYSICAL FACTORS

• PHYSIO-CHEMICAL FACTORS

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PHYSICAL FACTORS

• PARTICLE SIZE

• Smaller particle size, greater surface area
  then higher will be dissolution rate, because
  dissolution is thought to take place at the
  surface area of the solute( Drug).
• This study is imp. for drugs that have low
  aqueous solubility. Absorption of such drugs can
  be increased by increasing particle size by
  Micronization.
• ex. Griseofulvin, active intravenously but not
• effective when given orally.

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• To poor soluble drug, disintegration agents and
  surface active agents may be added .
• ex. Bioavailability of Phenacetin is increased
  by tween 80.
• Micronization also reduces the dose of some
  drugs
• ex. the dose of griseofulvin is reduced to one
  half while the dose of spironolactone is reduced
  to one twentieth.

• PARTICLE SIZE

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• Lesser particle size is always not helpful
• Ex. Micronization of Aspirin, phenobarbital,
  lesser effective
  surface area and hence lesser dissolution
  rate
• Reasons
• On their surface, hydrophobic drugs absorb air
  and reduce their wettability
• Particle having size below 0.1 micron
  reaggregate to form large particle
• Particle having certain micro size get
  electrical charge which preventing contact with
  wetting medium

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Finally drug size reduction and subsequent
increase in surface area and dissolution rate is
always not useful. Ex. of such drugs are
Penicillin G Erythromycin These Drugs are
unstable and degrade quickly in solution.
Sometime, reduction in particle size of
nitrofurantoin and piroxicam increase gastric
irritation These problem can be overcome by
Microencapsulation.
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2. Crystal Form Substance can exist
either in a crystalline or amorphous form. When
substance exist in more than one crystalline
form, the different form are called polymorphs
and the phenomena as polymorphism . Two types of
Polymorphism 1) Enantiotropic polymorph ex.
Sulfur 2) Monotropic polymorph ex. Glyceryl
Stearates Polymorphs have the same chemical
structure but different physical properties such
as solubility, density, hardness etc. ex.
Chlormphenicol has a several crystal form, and
when given orally as a suspension, the drug
concentration in the body was found to be
dependent on the percentage of ß - polymorph in
the suspension. The form is more soluble and
better absorbed.
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One of the several form of polymorphic forms is
more stable than other. Such a stable form having
low energy state and high melting point and least
aqueous solubility The remaining polymorphs are
called as metastable forms which have high energy
state, low melting point and high aqueous
solubilities. About 40 of all organic
compounds exhibit polymorphism. Some drug exists
in amorphous form which have no internal crystal
structure. Such drugs have high energy states
than crystal form hence they have greater aqueous
solubility than crystalline form. Ex. Novobiocin,
cortisone acetate.
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4. Complexation
This property can influence the effective drug
concentration in gi fluids. Complexation of
drug and gi fluids may alter the rate and
extent of absorption
eg. Intestinal Mucin form complex with
Streptomycin and Dihydro Streptomycin.
In some cases, Poor water soluble drugs can be
administered as water soluble complexes. eg.
Hydroquinone with Digoxin.
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5.Adsorption
It is a physical and surface phenomena where the
drug molecules are held on the surface of some
inert substances by vanderwalls forces.
ex. Charcoal used as an antidote When it is
co-administered with promazine, then it reduces
the rate and extent of absorption
Cholestyramine reduces the absorption of warfarin.
6.Drug Stability And Hydrolysis In GIT
Drugs undergoes various reactions due to wide
spectrum of ph and enzymatic activity of GI
fluid namely acid and enzymatic hydrolysis.
eg. T½ of Penicillin G 1 min. at pH 1
T½ of Penicillin G 9 min. at pH2 So it means
Penicillin G is stable at less acidic pH
Erythromycin and its esters are unstable at
gastric fluid (T½Less than 2 min.)
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• Certain salts also may have low solubility and
  dissolution rate.

8. Presence Of Surfactant
Use of wetting agent and Solubilizing agent
improve the Dissolution rate absorption of
drugs. Ex. Tween 80 increase the rate extent of
absorption of Phenacetin.
9. Dissolution
Disintegration is the formation of dispersed
granules from an intact solid dosage form whereas
the dissolution is the formation of solvated drug
molecules from the drug
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SOLID DRUG
DISSOLUTION
DRUG AT ABSORPTION SITE
ABSORPTION
DRUG IN SYSTEMIC CIRCULATION
85
NOYES AND WHITNEYS EQUATION
dc/dt KS(CS-C)
Where, dc/dt Rate constant, K constant,
S surface area of the dissolving solid,
Cssolubility of the drug in the solvent,
Cconcentration of drug in the solvent at time t.
Constant KD/h
Where, D is the diffusion coefficient of the
dissolving material and h is the thickness of
the diffusion layer
Here, C will always negligible compared to Cs
So, dc/dtDSCs/h
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PHYSICOCHEMICAL FACTORS

• 1) pH PARTITION THEORY (Brodie)
• It explain drug absorption from GIT and its
  distribution across biomembranes.
• Drug(gt100 daltons) transported by passive
  diffusion depend upon
• dissociation constant, pKa of the drug
• lipid solubility, K o/w
• pH at absorption site.
• Most drugs are either weak acids or weak bases
  whose degree of ionization is depend upon pH of
  biological fluid.

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• For a drug to be absorbed, it should be unionized
  and the unionized portion should be lipid
  soluble.
• The fraction of drug remaining unionized is a
  function of both
• Dissociation constant (pKa) and pH of solution.
• The pH partition theory is based on following
  assumption
• GIT acts as a lipoidal barrier to the transport
  of the drug
• The rate of absorption of drug is directly
  proportional to its fraction of unionised drug
• Higher the lipophilicity of the unionised
  degree, better the absorption.
  

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HENDERSON HASSELBATCH EQUATION For acid,
pKa - pH log Cu/Ci
For base, pKa pH
log Ci/Cu Eg. Weak acid aspirin (pKa3.5) in
stomach (pH1) will have gt 99of unionized form
so gets absorbed in stomach Weak base quinine
(pKa8.5) will have very negligible unionization
in gastric pH so negligible absorption
Several prodrugs have been developed which are
lipid soluble to overcome poor oral absorption of
their parent compounds.
89
eg. Pivampicilin, the pivaloyloxy-methyl ester
of ampicilin is More lipid soluble than
ampicilin. Lipid solubility is provided to a
drug by its partition coefficient between An
organic solvent and water or an aq. Buffer (same
pH of ab. Site) E.g. Barbital has a p.c. of
0.7 its absorption is 12
Phenobarbital ( p.c 4.8 absorption12)
Secobarbital (p.c 50.7 absorption40)
90
2)DRUG SOLUBILITY The absorption of drug
requires that molecule be in solution at
absorption site. Dissolution, an important step,
depends upon solubility of drug substance. pH
solubility profile pH environment of GIT varies
from Acidic in stomach to slightly Alkaline in a
small intestine.

soluble
1)Basic drug 1) Acidic
medium( stomach) 2)Acidic drug
2) basic medium( intestestine)
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• Improvement of solubility
• Addition of acidic or basic excipient
• Ex Solubility of Aspirin (weak acid) increased
  by addition of basic excipient.
• For formulation of CRD , buffering agents may be
  added to slow or modify the release rate of a
  fast dissolving drug.

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PHARMACEUTICAL FACTORS MEANS Absorption rate
depends on the dosage Form which is
administred,ingredients used, procedures Used in
formulation of dosage forms. The
availability of the drug for absorption from the
dosage forms is in order. Solutions gt
Suspensions gt capsules gt Compressed Tablets gt
Coated tablets.
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• SOLUTIONS
• Shows maximum bioavailability and factors
  affecting
• Absorption from solution are as follows
• Chemical stability of drug
• Complexation between drug and exipients of
  formulation
• to increase the solubility, stability.
• 3. Solubilization incorporation of drug into
  micelles to increase the solubility of drugs.
• 4. Viscosity
• 5. Type of solution Whether aqueous or oily
  solution.

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• SUSPENSIONS
• It comes next after solutions with respect to
  bioavailability
• Factors that affects absorption from
  suspensions are
• Particle size and effective surface area of
  dispersed phase
• 2. Crystal form of drug some drug can change
  their crystal
• structure.
• Eg. Sulfathiazole can change its polymorphic
  form, it can be
• overcome by addition by adding PVP.
• 3. Complexation Formation of nonabsorbable
  complex between
• drug and other ingredients.
• Eg. Promazine forms a complex with
  attapulgite.

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4. Inclusion of surfactant Eg. The
absorption of phenacitin from suspension is
increased in presence of tween 80. 5.
Viscosity of suspension Eg. Methyl cellulose
reduces the rate and absorption of
nitrofurantoin 6. Inclusion of colourants
Eg. Brilliant blue in phenobarbitone suspension.
96

• CAPSULES
• Two types of capsule
• Hard gelatin capsule
• 2. Soft gelatin capsule

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HARD GELATIN CAPSULE The rate of absorption of
drugs from capsule is function Of some
factors. 1.Dissolution rate of gelatin
shell. 2.The rate of penetration of GI fluids
into encapsulated mass 3.The rate at which the
mass disaggregates in the GI fluid 4. The rate of
dissolution. 5. Effect of excipients a).Diluents
b).Lubricants c). Wetting characteristics of
drug d).Packing density
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SOFT GELATIN CAPSULE SGS has a gelatin shell
thicker than HGS,but shell is Plasticized by
adding glycerin,sorbitol.SGS may used To contain
non aqueous solution or liquid or semi
solid. SGC have a better bioavailability than
powder filled HGC And are equivalent to
emulsions. Eg. Quinine derivative was better
absorbed from SGC Containing drug base compared
with HGC containing HCl salts. Grieseoflavin
exhibited 88 absorption from soft
gelatin Capsules compared to HGC(30)
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TABLETS 1.Compressed tablets 2. Coated tablets
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Compressed tablets Bioavailability are more due
to large reduction in surface area.
A
B
Intact tablets a granules
primary drug particles
K2
K1
K3
Drug in GI fluid
K4
Drug absorbed in body
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The rate constants decrease in the following
order.
K3gtgtK2gtgtK1 The overall dissolution rate and
bioavailability of a poor Soluble drugs is
influenced by 1.The physicochemical properties of
liberated particles. 2. The nature and quantity
of additives. 3. The compaction pressure and
speed of compression. 4. The storage and age of
tablet
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1.Effect of diluents Na Salicylates starch
Faster dissolution Na salicylates
lactosePoor dissolution. 2.Effect of
Granulating agent Phenobarbital Gelatin
solutionFaster dissolution PhenobarbitalPEG
6000 poor dissolution. 3.Effect of
lubricants Magnesium stearate will retard the
dissolution of aspirin tablet Whereas SLS
enhance the dissolution.
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4.Effect of disintegrants Starch tend to swell
with wetting and break apart the dosage form. It
is reported that 325mg of salicylic acid tablet
were prepared by using different concentrations
(5,10,20) and max. dissolution was achieved
With 20 starch. 5. Effect of
colorants 6.Effect of Compression force
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COATED TABLETS There are three types of
coating Sugar coating Film coating Enteric
coating SUGAR COATING Sugar,Shellac,fatty
glycerides, bees wax, silicone resin Sub coating
agent Talc,acacia,starch. FILM
COATING Polymers, dispersible cellulose
derivatives like HPMC CMC. ENTERIC
COATING Shellac, cellulose acetate phthalate etc.
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Factors affecting the drug release
are 1.Thickness of coating e.g.. Quinine shows
decrease in rate of absorption if coated with
cellulose acetate phthalate. 2.The amount of
dusting powder 3.Effect of ageing e.g. The
shellac coated tablets of Para amino
salicylic acid when given after two years plasma
concentration of 6-7mg/100ml. However the tablets
stored for 3½ years showed plasma concentration
of only 2mg/100ml which is the sub therapeutic
effect.
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SUBLINGUAL / BUCCAL ROUTE
SUBLINGUAL / BUCCAL ROUTE

• SUBLINGUAL ROUTE the dosage form is placed
  beneath the tongue.
• BUCCAL ROUTE Dosage form is placed between the
  cheek and teeth or In the cheek pouch.
• Drugs administered by this route are supposed to
  produce systemic drug effects, and consequently,
  they must have good absorption from oral mucosa.
• Oral mucosal regions are highly vascularised
  therefore rapid onset of action is observed.
• For Eg, anti-anginal drug Nitroglycerin.

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• SUBLINGUAL / BUCCAL ROUTE
• Blood perfuses oral regions drains directly into
  the general circulation.
• Barrier to drug absorption from these routes is
  epithelium of oral mucosa.
• Passive diffusion is the major mechanism of
  absorption of most drugs.
• In general, sublingual tablets are designed to
  dissolve slowly to minimize possibility of
  swallowing the dose.
• Exception include Nitroglycerin, Isosorbide
  dinitrate tablets which dissolves within minutes
  in buccal cavity to provide prompt treatment of
  acute anginal episodes.

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Factors to be considered

• Lipophilicity of drug The lipid solubility
  should be high for absorption.
• Salivary secretion drug should be soluble in
  buccal fluid.
• pH of saliva pH of saliva is usually 6.
• Storage compartment some drugs have storage
  compartment in buccal mucosa. Eg, Buprenorphine
• Thickness of oral epithelium Sublingual
• absorption is faster than buccal, because
  former region is thinner than that of buccal
  mucosa.

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FACTORS LIMITTING DRUG ADMINISTRATION

• Limited mucosal surface area.
• Taste of medicament and discomfort.
• EXAMPLES Nitroglycerin, Isosorbide
  dinitrate, Progesterone, Oxytocin, Fenosterol,
  Morphine.

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RECTAL ADMINISTRATION

• Absorption across the rectal mucosa occurs by
  passive diffusion.
• This route of administration is useful in
  children, old people and unconscious patients.
• Eg., drugs that administered are aspirin,
  acetaminophen, theophylline, indomethacin,
  promethazine certain barbiturates.

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PARENTERAL ROUTES

• .

114
INTRAVENOUS ROUTE
INTRAVENOUS ROUTE

• Absorption phase is bypassed
• (100 bioavailability)
• 1.Precise, accurate and almost immediate onset of
  action,
• 2. Large quantities can be given, fairly pain
  free
• 3. Greater risk of adverse effects
• a. High concentration attained rapidly
• b. Risk of embolism

115
INTRAVENOUS ROUTE

• This route is used when a rapid clinical response
  is required like treatment of epileptic seizures,
  acute asthmatic and cardiac arrhythmias.
• There may also be a danger of precipitation of
  drug in the vein if the inj. is too rapidly. This
  could result in thrombophlebitis.
• This mode of administration is required with
  drugs having short half lives and narrow
  therapeutic index.
• Bioavailability is not considered by this route.
• Mainly antibiotics are administered by this route.

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Intra arterial injection

• In this route the drugs are injected directly
  into the artery.
• It is mainly used for cancer chemotherapy.
• It increased drug delivery to the area supplied
  by the infused artery and decreased drug delivery
  to systemic circulation.

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INTRA MUSCULAR INJECTION

• Absorption of drug from muscles is rapid and
  absorption rate is perfusion rate limited.
• Polypeptides of less than approx 5000 gram per
  mole primarily pass through capillary pathway
• Greater than about 20000 g/mol are less able to
  traverse capillary wall, they primarily enter
  blood via lymphatic pathway.

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Factors determining rate of drug absorption

• 1. Vascularity to the inj. Site
• Blood flow rates to intramuscular tissues
  are
• Arm (deltoid) gt thigh (vastus lateralis) gt
  buttocks (gluteus maximus).
• 2. Lipid solubility and ionisation of drug.
• 3. Molecular size of drug.
• 4. Volume of inj. And drug concentration.
• 5. pH viscosity of inj. vehicle.

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SUBCUTANOUS ROUTE 1. Slow and
constant absorption 2. Absorption is limited by
blood flow, affected if
circulatory problems exist. 3. The blood supply
to this is poorer than that of muscular
tissue. 4. Concurrent administration of
vasoconstrictor will slow absorption, e.g.
Epinephrine. 5. The absorption is hastened by
massage, application of heat to increase
blood flow and inclusion of enzyme Hyaluronidase
in drug solution. eg. Insulin.
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• TOPICAL ADMINISTRATION
• MUCOSAL MEMBRANES(eye drops, antiseptic,
  sunscreen, nasal, etc.)
• SKIN
• a. Dermal - rubbing in of oil or ointment
  (local action)
• b. Transdermal - absorption of drug through
  skin (systemic action)
• i. stable blood levels
• ii. no first pass metabolism
• iii. drug must be potent.

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• Skin consist of three layers
• Epidermis
• Dermis
• Subcutaneous fat tissue
• The main route for the penetration of the drugs
  is generally through epidermal layer
• Stratum corneum is the rate limiting barrier in
  passive percutaneous absorption of drug.

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• The stratum corneum is the outermost layer of
  the epidermis and is composed mainly of dead
  keratinized cells (from lack of oxygen and
  nutrients). It has a thickness between 10 - 40
  µm.
• The dermis is the layer of skin beneath the
  epidermis. It contains the hair follicles, sweat
  glands, sebaceous glands, apocrine glands,
  lymphatic vessels and blood vessels.
• Hypodermis - Its purpose is to attach the skin
  to underlying bone and muscle as well as
  supplying it with blood vessels and nerves. The
  main cell types are fibroblasts, macrophages and
  adiposities (the hypodermis contains 50 of body
  fat).

124

125
OCULAR ADMINISTRATION

• Eye is the most easily accessible site for
  topical administration of a medication.
• Topical application of drug to eyes meant for
• Mydriasis, miosis, anaesthesia, treatment of
  infection, glaucoma etc.
• Opthalmic solution are administered into
  cul-de-sac.
• Barrier to intra occular penetration is cornea.
  It possess both hydrophilic and lipophilic
  characterstics.
• pH of lacrimal fluid is 7.4.
• pH of lacrimal fluid influences absorption of
  weak electrolyte like Pilocarpine.

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OCULAR ADMINISTRATION

• High pH of formulation decrease tear flow and
• Low pH of formulation increases tear flow.
• Human eye can hold around 10 microlitre of
  fluid. So small volume in concentrated form
  increases effectiveness.
• Viscosity empartners increases bioavailability
  eg, oily solutions, ointment etc.
• Systemic entry of drug occur by lacrimal duct
  which drains lacrimal fluid into nasal cavity.

127
Composition of eye

• Water - 98
• Solid -1.8
• Organic element
• Protein - 0.67, sugar - 0.65, Nacl - 0.66
• Other mineral element sodium, potassium and
  ammonia - 0.79

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Characteristics required to optimize ocular drug
delivery system

• Good corneal penetration.
• Prolong contact time with corneal tissue.
• Simplicity of instillation for the patient.
• Non irritative and comfortable form (viscous
  solution should not provoke lachrymal secretion
  and  reflex blinking)
• Appropriate rheological properties
  concentrations of the viscous system.

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Advantages

• Increase ocular residence.. Improving
  bioavailability
• Prolonged drug release.. better efficacy
• Less visual systemic side effects
• Increased shelf life
• Exclusion of preservatives
• Reduction of systemic side effects
• Reduction of the number of administration
• Better patient compliance
• Accurate dose in the eye. a better therapy

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FACTOR INFLUENCING PERCUTANEOUS ABSORPTION

• Drug release from dosage form
• Drug concentration in the formulation
• Drug oil water partition coefficient.
• Drug affinity to the skin tissue
• Surface area
• Site of application
• Hydration of skin
• Nature of vehicle used

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FACTOR INFLUENCING PERCUTANEOUS ABSORPTION

• 9. Rubbing
• 10. Contact period
• 11. Permeation enhancers

133
INHALATIONAL ROUTE 1.Gaseous and
volatile agents and aerosols. 2.Rapid onset of
action due to rapid access to circulation
a.Large surface area b.Thin membranes
separates alveoli from circulation
c.High blood flow Particles larger than 20
micron and the particles impact in the mouth and
throat. Smaller than 0.5 micron and they aren't
retained.
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• Intra nasal administration
• Drugs generally administered by intra nasal route
  for treatment of local condition such as
  perennial rhinitis, allergic rhinitis and nasal
  decongestion etc.
• Absorption of lipophilic drugs through nasal
  mucosa by passive diffusion and absorption of
  polar drugs by pore transport.
• Rate of absorption of lipophilic drugs depend on
  their molecular weight.
• Drugs with molecular weight less than 400 daltons
  exhibit higher rate of absorption.

135

• cont
• Drugs with molecular weight 1000 daltons show
  moderate rate of absorption.
• Presently nasal route is becoming popular for
  systemic delivery of peptide and proteins, this
  is because of high permeability of nasal mucosa
  with vasculature.

136

137
Advantages

• Rapid drug absorption via highly-vascularized
  mucosa
• Rapid onset of action
• Ease of administration, non-invasive
• Avoidance of the gastrointestinal tract and
  first-pass metabolism
• Improved bioavailability
• Lower dose/reduced side effects
• Improved convenience and compliance
• Self-administration.

138
Disadvantages

• Nasal cavity provides smaller absorption surface
  area when compared to GIT.
• Relatively inconvenient to patients when compared
  to oral delivery since there is possibility of
  nasal irritation.
• The histological toxicity of absorption enhancers
  used in the nasal drug delivery system is not yet
  clearly established.

139
Enhancement in absorption

• Following approaches used for absorption
  enhancement -
• Use of absorption enhancers
• Increase in residence time.
• Administration of drug in the form of
  microspheres.
• Use of physiological modifying agents

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Enhancement in absorption

• Use of absorption enhancers-
• Absorption enhancers work by increasing the
  rate at which the drug pass through the nasal
  mucosa.
• Various enhancers used are surfactants, bile
  salts, chelaters, fatty acid salts,
  phospholipids, cyclodextrins, glycols etc.

141
Various mechanisms involved in absorption
enhancements are-

• Increased drug solubility
• Decreased mucosal viscosity
• Decrease enzymatic degradation
• Increased Paracellular transport
• Increased transcellular transport

142
Various mechanisms involved in absorption
enhancements are-

• Increase in residence time-
• By increasing the residence time the
  increase in the higher local drug concentration
  in the mucous lining of the nasal mucosa is
  obtained.
• Various mucoadhesive polymers like
  methylcellulose, carboxy methyl cellulose or
  polyarcylic acid are used for increasing the
  residence time.

143
Various mechanisms involved in absorption
enhancements are-

• Use of physiological modifying agents-
• These agents are vasoactive agents and exert
  their action by increasing the nasal blood flow.
• The example of such agents are histamine,
  leukotrienene D4, prostaglandin E1 and
  ß-adrenergic agents like isoprenaline and
  terbutaline.

144
Applications of nasal drug delivery

• Nasal delivery of organic based pharmaceuticals
  -
• Various organic based pharmaceuticals have been
  investigated for nasal delivery which includes
  drug with extensive presystemic metabolism.
• E.g. Progesterone, Estradiol, Nitroglycerin,
  Propranolol, etc.

145
Applications of nasal drug delivery

• Nasal delivery of peptide based drugs -
• Nasal delivery of peptides and proteins is depend
  on
• The structure and size of the molecule.
• Nasal residence time
• Formulation variables (pH, viscosity)
• E.g. calcitonin, secretin, albumins, insulin,
  glucagon, etc.

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• PULMONARY ADMINISTRATION
• The drugs may be administered for local action of
  bronchioles or their systemic effects through
  absorption of lungs.
• Inhalation sprays and aerosols are used to
  deliver the drugs to the lungs.
• Larger surface area of alveoli, high permeability
  of alveolar epithelium for drug penetration, and
  a rich vasculature are responsible for rapid
  absorption of drugs by this route

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• PULMONARY ADMINISTRATION
• In general particles greater than 10mm are
  retained in the throat and upper airways whereas
  fine particles reach the pulmonary epithelium
• Drugs generally administered by this route are
  bronchodilators (e.g.. Salbutamol,
  isoproterenol), antiallergic (e.g.. Cromolym
  sodium), and antiinflammatory (e.g..
  Betamethasone, dexamethasone).

148

149
Advantages

• Smaller doses can be administered locally.
• Reduce the potential incidence of adverse
  systemic effect.
• It used when a drug is poorly absorbed orally,
  e.g. Na cromoglicate.
• It is used when drug is rapidly metabolized
  orally, e.g. isoprenaline

150
IN-VITRO METHODS

• Everted small intestine sac method.
• Everted sac modification.
• Circulation technique.
• Everted intestinal ring or slice technique.

151
Why in-vitro studies

• Because of economical ethical limitations of
  in-vivo studies.
• Simple provide valuable information.
• To assess the major factors involved in
  absorption.
• Predict the rate extent of drug absorption.
• Procedures are of great value during screening of
  new drug candidates.
• Carried out outside the body.
• Used to assess permeability of drug using animal
  tissues.

152
Everted small intestine sac technique
Isolation of rat intestine
Inverting the intestine
Filling the sac with drug free buffer solution
Immersion of sac in Erlenmeyer flask containing
drug buffer solution
Contd
153
Flask its contents oxygenated agitated at
37oC for specific period of time
After incubation, the serosal content is assayed
for drug content
154
Figure( reverted sac technique)
Serosal side
Mucosal side
(intestinal segment before eversion)
Serosal side
Buffer solution
Ligature
Mucosal side
(after eversion)
155
Advantages

• Prolongs the viability integrity of the
  preparation after removal from the animal.
• Convenience accuracy with respect to drug
  analysis.
• The epithelial cells of the mucosal surface are
  exposed directly to the oxygenated mucosal fluid.

DISADVANTAGES

• Difficulty in obtaining more than one sample per
  intestinal segment

156
Everted sac modification

• Crane Wilson modification.
• Essential features of simple sac methods are
  retained.
• Modification- the intestine is tied to a cannula.

157
cannula
Plain buffer
Buffer solution with drug
Water maintained at 37o C
aerator
(FIG EVERTED SAC MODIFICATION)
158
Procedure
Animal fasted for 20-24hrs
Water is allowed ad libitum
Animal killed with blow on head or anesthetized
with ether or chloroform
Entire small intestine is everted
Contd.
159
Segments of 5-15cm length are cut from specific
region of the intestine
Distal ends tied proximal end is attached to
cannula
Segments suspended in 40-100ml of drug mucosal
solution.
About 1ml/5cm length of drug free buffer is then
placed in serosal compartment
Mucosal solution aerated
160
How to determine the rate of drug transfer

• The entire volume of serosal solution is removed
  from the sac at each time interval with the help
  of syringe it is replaced with fresh buffer
  solution.
• The amount of drug that permeates the intestinal
  mucosa is plotted against time to describe the
  absorption profile of the drug at any specific pH.

161
Advantages

• A number of different solutions may be tested
  with a single segment of the intestine unlike in
  the sac technique.
• Simple reproducible.
• It distinguishes between active passive
  absorption.
• It determines the region of the small intestine
  where absorption is optimal, particularly in the
  case of active transport.
• Also used to study the effect of pH, surface
  active agents, complexation enzymatic reaction.

162
Disadvantages

• The intestinal preparation is removed from the
  animal as well as from its blood supply. Under
  these conditions, the permeability
  characteristics of the membrane are significantly
  altered.
• The rate of transport of drug as determined from
  the everted sac technique, may be slower than in
  the intact animal.

163
Circulation technique

• Small intestine may or may not be everted.
• In this method either entire small intestine of
  small lab animal or a segment is isolated.
• Oxygenated buffer containing the drug is
  circulated through the lumen.
• Drug free buffer is also circulated on the
  serosal side